Process and intermediates for the preparation of 3-(amino)-3-cyclobutylmethyl-2-hydroxy-propionamide or salts thereof

ABSTRACT

In one embodiment, the present application relates to a process of making a compound of formula I:  
                 
and to certain intermediate compounds that are made within the process of making the compound of formula I.

PRIORITY APPLICATION

This patent application claims the benefit of priority from U.S.provisional application Ser. No. 60/479,487 filed Jun. 17, 2003.

FIELD OF THE INVENTION

This invention relates to the process and intermediates for thepreparation of 3-(amino)-3-cyclobutylmethyl-2-hydroxy-propionamide orsalts thereof having the following structure (formula I):

or salts thereof.

BACKGROUND OF THE INVENTION

3-(Amino)-3-cyclobutylmethyl-2-hydroxy-propionamide is disclosed in U.S.patent application Ser. Nos. 09/908,955 which was filed Jul. 19, 2001,and Ser. No. 10/052,386 which was filed Jan. 18, 2002, which are eachincorporated herein by reference.

The compound of formula I is a key intermediate used in the preparationof the hepatitis C virus (“HCV”) protease inhibitor(1R,2S,5S)-3-azabicyclo[3,1,0]hexane-2-carboxamide,N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-2-[[[1,1-dimethylethyl)amino]carbonylamino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethylhaving the following structure:

The compound of formula Z disclosed in the above-noted patentapplications is useful for treating hepatitis C and related disorders.Specifically, the compound of formula Z is an inhibitor of the HCVNS3/NS4a serine protease.

There remains a need for methods of synthesizing compounds useful in thetreatment or prevention or amelioration of one or more symptoms ofhepatitis C.

In view of the importance of hepatitis C virus (“HCV”) proteaseinhibitors, new, novel methods of making such antagonists are always ofinterest.

SUMMARY OF THE INVENTION

In one embodiment, the present application relates to a process ofmaking a compound of formula I:

or salts thereof.

The invention also relates to certain intermediate compounds that aremade within the process of making the compound of formula I.

The process of making the compound of formula I comprises:

-   -   (1) alkylating and deprotecting a compound of formula II to        yield a compound of formula III:        wherein R represents an alkyl group or substituted alkyl group;    -   (2) protecting the compound of formula III with protecting        group (P) to yield a compound of formula IV:    -   (3) reducing the compound of formula IV to yield a compound of        formula V:    -   (4) oxidizing the compound of formula V to yield a compound of        formula VI:    -   (5) reacting the compound of formula VI with        to yield a compound of formula VII:    -   (6) hydrating the compound of formula VII to yield a compound of        formula VIII:    -   (7) deprotecting the compound of formula VIII to yield the        compound of formula I:        or salts thereof.

The inventive process to make the compound of formula I has severaladvantages: It is more suitable for scale up for manufacture, and it ismore cost effective. 4

DESCRIPTION OF THE INVENTION

As used above, and throughout the specification, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. The term “substitutedalkyl” means that the alkyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of halo, alkyl, cyano,hydroxy, alkoxy, alkylthio, amino, —NH(alkyl), —N(alkyl)₂, carboxy and—C(O)O-alkyl. Non-limiting examples of suitable alkyl groups includemethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl,nonyl, decyl, fluoromethyl, and trifluoromethyl.

“Halo” means fluoro, chloro, bromo, or iodo groups. Preferred arefluoro, chloro or bromo, and more preferred are fluoro and chloro.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred arefluorine, chlorine or bromine, and more preferred are fluorine andchlorine.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy.The bond to the parent moiety is through the ether oxygen.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio, ethylthio, i-propylthio and heptylthio. The bond tothe parent moiety is through the sulfur.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Non-limiting examples of suitablesolvates include ethanolates, methanolates, and the like. “Hydrate” is asolvate wherein the solvent molecule is H₂O.

In one embodiment, the present invention relates to a process forpreparing the compound of formula I. The inventive process isschematically described in Scheme I below:

R represents an alkyl or substituted alkyl group. Non-limiting examplesof alkyl groups are (C₁-C₁₂)alkyl, (C₁-C₆)alkyl, and (C₁-C₃)alkyl.

P is a protecting group. Examples of N-protecting groups suitable in thepractice of the invention include allyl, methoxymethyl, benzyloxymethyl,CY₃CO (where Y is a halogen), benzyloxycarbonyl, trityl,pivaloyloxymethyl, tetrahydranyl, benzyl, di(p-methoxyphenyl)methyl,triphenylmethyl, (p-methoxyphenyl)diphenylmethyl, diphenylphosphinyl,benzenesulfenyl, methylcarbamate, 2-trimethylsilylethyl carbamate,1-methyl-1-phenylethyl carbamate, t-butyl carbamate (“t-Boc”),cyclobutyl carbamate, 1-methylcyclobutyl carbamate, adamantyl carbamate,vinyl carbamate, allyl carbamate, cinnamyl carbamate, 8-quinolylcarbamate, 4,5-diphenyl-3-oxazolin-2-one, benzyl carbamate,9-anthrylmethyl carbamate, diphenylmethyl carbamate andS-benzylcarbamate.

Preferred N-protecting groups include methylcarbamate,2-trimethylsilylethyl carbamate, 1-methyl-1-phenylethyl carbamate,t-butyl carbamate (“t-Boc”), cyclobutyl carbamate, 1-methylcyclobutylcarbamate, adamantyl carbamate, vinyl carbamate, allyl carbamate,cinnamyl carbamate, 8-quinolyl carbamate, benzyl carbamate,9-anthrylmethyl carbamate, diphenylmethyl carbamate, S-benzylcarbamate,more preferably t-Boc.

Step 1:

To a solution of 35.0 kg (131 mol) of a compound of formula II in asuitable solvent at a temperature ranging from about −20° C. to about70° C., preferably from about 0° C. to about 50° C., more preferablyfrom about 20° C. to about 30° C., is added suitable base. Non-limitingexamples of suitable bases that can be used include metal hydrides,alkyl lithium and metal alkoxides. Preferred bases are metal alkoxides.The metal in either the metal alkoxide or the metal hydride can besodium, potassium, and the like. The alkoxide can contain from 1 to 12carbon atoms, preferably from 1 to 6 carbon atoms, more preferably from1 to 4 carbon atoms. An example of a preferred metal alkoxide includespotassium tert-butoxide. Examples of alkyl lithium bases include lithiumdiethylpropylamide and butyl lithium. Non-limiting examples of thesuitable solvents include, aromatic solvents, hydrocarbon solvents andether solvents. Non-limiting examples of aromatic solvents includebenzene, xylene, and toluene. Non-limiting examples of hydrocarbonsolvents include pentane, hexane and heptane. Non-limiting examples ofether solvents include THF, TBME, and diethylether. Preferred solventsare ether solvents such as THF, TBME, and diethylether, more preferablyTHF. The mixture is then agitated for about 1 hour or until the reactionis 7 complete at a temperature ranging from about −45° C. to about 40°C., preferably from about −25° C. to about 20° C., more preferably fromabout −5° C. to about 0° C. (Halomethyl)cyclobutane or(sulfonatemethyl)cyclobutane is then added,preferably(halomethyl)cylcobutane), more preferably(bromomethyl)cyclobutane. The (halomethyl)cyclobutane can be usedgenerally from about 0.2 to about 10 molar equivalents with respect tothe compound of formula II, preferably from about 1 to about 5 molarequivalents, and more preferably from about 1 to about 1.5 molarequivalents. Any excess of (halomethyl)cyclobutane can be used. Themixture is then agitated for 24 hours or until the reaction is completeat a temperature ranging from about −20° C. to about 65° C., preferablyfrom about 0° C. to about 45° C., more preferably from about 20° C. toabout 25° C. After this period of time, an aqueous solution of acid isadded. Non-limiting examples of acids that can be added includeinorganic or organic acids such as ammonium sulfate, ammonium nitrate,ammonium chloride, H₂SO₄, HCl, H₃PO₄, citric acid, mesyl chloride,paratoluenesulfonic acid, paratoluenesulfonic acid pyridinium salt,alkylsulfonic acid, and the like, or mixtures thereof. Preferred acidsare inorganic acids such as H₂SO₄, HCl, and H₃PO₄, preferably HCL. Theresulting mixture was agitated for 2 hours or until the reaction iscomplete to provide a compound of formula III.

Step 2:

An N-protecting group (P) in a suitable solvent (24.9 kg, 131 mol) isadded to the compound of formula III from step 1. The N-protecting groupcan be used generally from about 0.2 to about 10 molar equivalent withrespect to the compound of formula III, preferably from about 1 to about5 molar equivalents, and more preferably from about 1 to about 1.5 molarequivalents. Non-limiting examples of the suitable solvents that can beused in step 2 include aromatic solvents, hydrocarbon solvents and ethersolvents. Preferred solvents are ether solvents such as THF, TBME, anddiethylether, more preferably THF.

After the addition, the reaction mixture is adjusted to a temperatureranging from about −20° C. to about 65° C., preferably from about 0° C.to about 45° C., more preferably from about 20° C. to about 25° C. andagitated for about 4 hours or until the reaction is complete to yield acompound of formula IV.

Step 3:

A solution of a reducing agent in a suitable solvent is added to thecompound of formula IV from step 2. Non-limiting examples of reducingagents include metal hydrides such as lithium aluminum hydride (LiAlH₄),lithium borohydride (LiBH₄) or sodium borohydride (NaBH₄). The reducingagent can be used generally from about 0.1 to about 10 molar equivalentswith respect to the compound of formula IV, preferably from about 0.25to about 5 molar equivalents, and more preferably from about 1 to about2 molar equivalents. Any excess of reducing agent can be used.Non-limiting examples of suitable solvents that can be used in step 3include aromatic solvents, hydrocarbon solvents and ether solvents.Preferred solvents are ether solvents such as THF, TBME, anddiethylether, more preferably THF. The resulting mixture is agitated forabout 6 hours or until the reaction is complete to yield a compound offormula V.

Step 4:

To the compound of formula V from step 3 in a suitable solvent is slowlyadded an oxidizing agent capable of oxidizing the alcohol group offormula V into an aldehyde group. Preferably, one or more catalysts anda base is added prior to the oxidizing agent. A preferred combination ofcatalysts, base and oxidizing agent includes2,2,6,6-Tetramethyl-1-piperidinyloxy (TEMPO) and a metal bromide each ascatalysts, wherein the metal of the metal bromide can be Na, K, Li andthe like, sodium bicarbonate as the base, and sodium hypochlorite as theoxidizing agent. The oxidizing agent can be used generally from about0.2 to about 10 molar equivalents with respect to the compound offormula V, preferably from about 1 to about 5 molar equivalents, andmore preferably from about 1 to about 1.5 molar equivalents.Non-limiting examples of suitable solvents include hydrocarbon solvents,ester solvents, aromatic solvents, THF, and the like, or mixturesthereof. Preferred solvents include the ester solvents, more preferablyisopropyl acetate or ethyl acetate. The reaction mixture is stirred forabout 30 minutes or until the reaction is complete to yield a compoundof formula VI.

Step 5:

To the compound of formula VI from step 4 is added a phase transfercatalyst and a cyanide catalyst such as potassium cyanide, sodiumcyanide and the like. Non limiting examples of phase transfer catalystsinclude tetrabutyl ammonium iodide, tetrabutyl ammonium bromide, methyltricapryl ammonium chloride, triethyl benzyl ammonium chloride,tetrabutyl ammonium hydrogen sulfate, methyl tributyl ammonium chloride,tetraphenyl phosphonium bromide, tetrabutyl phosphonium bromide, PEG-500demethyl ether, butyl diglyme, and dibenzo-18-crown-6. Acetonecyanohydrin is added at a temperature ranging from about −25° C. toabout 60° C., preferably from about −5° C. to about 40° C., morepreferably from about 15° C. to about 20° C. The acetone cyanohydrin canbe used generally from about 0.2 to about 10 molar equivalents withrespect to the compound of formula VI, preferably from about 1 to about5 molar equivalents, and more preferably from about 1 to about 1.5 molarequivalents. The mixture is stirred for about 2 hours or until thereaction is complete to yield a compound of formula VIII.

Step 6:

A base in an appropriate solvent and DMSO is added to the compound offormula VII from step 5. An example of an appropriate solvent includesacetone. Non-limiting Examples of appropriate bases include KCO₃ orNaCO₃. The reaction mixture is heated to a temperature ranging fromabout 25° C. to about 105° C., preferably from about 45° C. to about 85°C., more preferably from about 60° C. to about 70° C. Hydrogen peroxideis then slowly added to the reaction mixture to yield a compound offormula VIII. Other methods of hydration can be used to convert thecompound of formula VII to the compound of formula VIII such as the useof MnO₄, or an enzyme that catalyzes hydration.

Step 7:

To the compound of formula VIII from step 6 in a suitable solvent isadded an acid. Non-limiting examples of acids that can be added includeinorganic or organic acids such as ammonium sulfate, ammonium nitrate,ammonium chloride, trifluoroacetic acid (TFA), H₂SO₄, HCl, H₃PO₄, citricacid, mesyl chloride, paratoluenesulfonic acid, paratoluenesulfonic acidpyridinium salt, alkylsulfonic acid, and the like, or mixtures thereof.Preferred acids include TFA, H₂SO₄, HCl, and H₃PO₄, more preferably TFAor HCl. After the addition of acid, the mixture is heated to atemperature ranging from about 0° C. to about 90° C., preferably fromabout 20° C. to about 70° C., more preferably from about 40° C. to about50° C. and agitated for about 4 hours or until the reaction is completeto yield a compound of formula I or salts thereof. A preferred salt ofthe compound of formula I is the following:

The following non-limiting EXAMPLES are provided in order to furtherillustrate the present invention. It will be apparent to those skilledin the art that many modifications, variations and alterations to thepresent disclosure, both to materials, methods and reaction conditions,may be practiced. All such modifications, variations and alterations areintended to be within the spirit and scope of the present invention

EXAMPLES

Unless otherwise stated, the following abbreviations have the statedmeanings in the Examples below:

-   MHz=Megahertz-   NMR=nuclear magnetic resonance spectroscopy-   mL=milliliters-   g=grams-   THF=tetrahydrofuran-   TFA=trifluoroacetic acid-   TEMPO=2,2,6,6-Tetramethyl-1-piperidinyloxy-   DMSO=dimethylsulfoxide-   TBME=t-butylmethyl ether-   t-Boc=t-butyl carbonate    Step 1:

To a solution of 35.0 kg (131 mol) of (diphenylmethylene) glycine ethylester II in 158 L of THF at −20° C. to −30° C. was added a solution of17.9 kg (160 mol) of potassium tert-butoxide in 158 L of THF. After theaddition, the mixture was warmed to −5° C. to 0° C. and agitated for 1hour, and 18 L (162 mol) of (bromomethyl)cyclobutane was added. Afterthe addition, the mixture was further warmed to 20° C. to 25° C. andagitated for 24 hours. After this period of time, a solution of 35 L ofHCl (37% in 140 L of water) was added. The resulting mixture wasagitated for 2 hours, then settled, and separated. Organic layer waswashed with 105 L of water. Aqueous layers were combined and washed with280 L of TBME twice. After washes, to the aqueous layer was added 175 Lof TBME and a solution of 52.5 kg of potassium carbonate in 105 L ofwater. The resulting mixture was agitated for 30 minutes, settled, andseparated. The aqueous layer was extracted with 175 L of TBME to yieldan organic layer containing the compound of formula III.

Step 2:

The combined organic layer from step 1 was concentrated to a volume of140 L and cooled to 0° C. to 5° C. Di-tert-butyldicarbonate (75% wt.solution in THF) (24.9 kg, 131 mol) was added. After the addition, themixture was warmed to 20° C. to 25° C., agitated for 4 hours, and washedwith 70 L of water. The organic layer was dried via azeotropicdistillation, concentrated to a volume of 140 L, and cooled to 30° C. to35° C. to yield the compound of formula IV.

Step 3:

A solution of lithium borohydride in THF (2.0M) (58.5 kg, 131 mol) wasadded to the compound of formula IV from step 2. The resulting mixturewas agitated for 6 hours and cooled to 15° C. to 20° C. The reaction wasquenched by addition of a solution of 17.5 kg of potassium dihydrogenphosphate in 175 L of water. After separation, the aqueous layer wasextracted with 105 L of TBME. The combined organic layers were washedwith water and sodium chloride solution. TBME in organic layer wasdisplaced with heptane via distillation and the product was crystallizedfrom the heptane solution. After filtration and drying, 13.0 kg of thecompound of formula V (43%) was obtained.

¹H NMR 400 MHz (CDCl3): δ 4.7 (1H), 3.6 (2H), 3.5 (1H), 2.8 (1H), 2.4(1H), 2.1 (2H), 1.9 (2H), 1.7 (2H), 1.6 (2H), and 1.5 (9H).

Step 4:

To a solution of 100.0 g (0.436 mole) of the compound of formula V fromstep 3 and TEMPO (1.0 g, 6.4 mmole) in ethyl acetate (1.0 L) was added asolution of lithium bromide (3.0 g, 34.5 mmole) and sodium bicarbonate(30 g, 0.357 mole) in water (500 ml). The mixture was cooled to −5 to 5°C. Sodium hypochlorite solution 15% (197.3 ml, 0.436 mole) was addedover 2 hours. After addition, the reaction mixture was stirred for 30minutes. Upon reaction completion, sodium thiosulfate (20 g, 80.6 mmole)was added, then the aqueous layer was separated to yield an ethylacetate layer containing the compound of formula VI.

Step 5:

To the ethyl acetate layer from step 4 were added tetrabutylammoniumiodide (1.0 g, 2.7 mmole) and potassium cyanide (4.0 g, 61.4 mmole) inwater (50 ml). At 15° C. to 25° C., acetone cyanohydrin (51.0 g, 0.599mole) was added. The mixture was stirred for 2 hours. Upon reactioncompletion, the aqueous layer was separated. Organic layer was thenwashed with 20% sodium chloride solution (350 ml) and concentrated toyield an ethyl acetate layer containing the compound of formula VII.

Step 6:

The ethyl acetate in the organic layer in step 5 was displaced with DMSO(250 ml) via distillation. Potassium carbonate (40 g, 0.289 mole) andacetone (700 ml) were added. The mixture was heated to reflux at about65° C. At reflux, 30% hydrogen peroxide (100 ml, 0.979 mole) was addedover 2 hours. Then the reaction mixture was stirred at reflux for 3hours. Upon reaction completion, water (800 ml) was added at 35° C. to45° C. The product precipitated during the addition. The mixture wascooled to 0° C. to 50° C. and filtered to give the product, designatedas PART 1, which was predominantly either the RR or SS isomer. ¹H NMR400 MHz (CDCl₃): δ 6.82 (s, 1H), 5.64 (s, 1H), 5.2 (m, 1H), 4.90 (d, J=8Hz, 1H), 4.21 (d, J=1.76 Hz, 1H), 3.72 (m, 1H), 2.37 (m, 1H), 2.07 (m,2H), 1.86 (m, 3H), 1.66 (m, 3H), 1.43 (s, 9H).

Acetone in the filtrate was removed through vacuum distillation. Ethylacetate (1.2 L) was added to extract the product. The ethyl acetateextract was washed in sequence with water twice and sodium chloridesolution. Ethyl acetate was removed through vacuum distillation. Therest of ethyl acetate was displaced with n-butyl acetate through vacuumdistillation. The product, PART 2, precipitated from butyl acetate andwas collected through filtration. This was predominantly either the RSor SR isomer. ¹H NMR 400 MHz (CDCl₃): δ 6.87 (s, 1H), 5.78 (s, 1H), 5.19(d, J=7.6 Hz, 1H), 4.09 (d, J=2.30 Hz, 1H), 3.72 (m, 1H), 2.36 (m, 1H),2.08 (m, 2H), 1.88 (m, 3H), 1.68 (m, 3H), 1.45 (s, 9H).

A total of 80 g (67.4%) of the combined PART 1 and PART 2 of thecompound of formula VIII was obtained.

Step 7:

To a mixture of 15.0 kg (55.1 mol) of the compound of formula VIII fromstep 6 in 135 L of isopropyl alcohol at 20° C. to 25° C. was added 30 Lof 5-6N HCl in isopropyl alcohol. After the addition, the mixture washeated to 40° C. to 50° C. and agitated for 4 hours. After this periodof time, the mixture was cooled to 0° C. to 5° C. and filtered. The wetcake was dried to give 10.9 kg of the hydrochloride salt of the compoundof the formula 1 (91%).

1H NMR 400 MHz (DMSO): δ 4.2 and 4.0 (1H), 3.3 and 3.1 (1H), 2.4 (1H),2.0 (2H), 1.8 (2H), and 1.6 (4H).

It will be understood that various modifications can be made to theembodiments and examples disclosed herein. Therefore, the abovedescription should not be construed as limiting, but merely asexemplifications of preferred embodiments. Those skilled in the art willenvision various modifications within the scope and spirit of the claimsappended hereto.

1-22. (canceled)
 23. A compound of the formula:


24. A compound of the formula: